Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
  • C07D213/30—Oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
  • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom

Definitions

• This invention relates to (pyridinyl)benzoxazol-2(3H)-ones, their preparation and their use as cardiotonics.
• Coates et al [J. Chem. Soc. 1943, 406] show the preparation of 4-(2-pyridinyl)-2-aminophenol in four steps from N-acetyl-4-(2-pyridinyl)aniline, the last two steps comprising converting 2-nitro-4-(2-pyridinyl)aniline to 2-nitro-4-(2-pyridinyl)phenol and reducing the latter to convert nitro to amino.
• Coates et al also show 3-(4-pyridinyl)phenol. Coates utilized said pyridinyl-phenols as intermediates to prepare pyridinyl-quinolines, which in turn were investigated for possible spasmolytic activity with disappointing results.
• the invention resides in a 5-(pyridinyl)benzoxazol-2(3H)-one or salt thereof, useful as a cardiotonic agent.
• the invention resides in the process which comprises reacting 2-amino-4-(pyridinyl)phenol with a carbonylating agent to produce 5-(pyridinyl)benzoxazol-2(3H)-one.
• the invention resides in a cardiotonic composition for increasing cardiac contractility which comprises a pharmaceutically-acceptable carrier and, as the active component thereof, a cardiotonically-effective amount of a 5(pyridinyl)benzoxazol-2(3H)-one or salt.
• the invention resides in a method for increasing cardiac contractility in a patient requiring such treatment which comprises administering to such patient a cardiotonically-effective amount of a 5-(pyridinyl)benzoxazol-2(3H)-one or salt.
• the invention resides in 5-PY-benzoxazol-2(3H)-one having formula I ##STR1## or pharmaceutically-acceptable acid-addition or cationic salt thereof were PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents. These compounds are useful as cardiotonic agents, as determined by standard cardiotonic evaluation procedures. Preferred embodiments are the compounds of formula I where PY is 4-pyridinyl and 3-pyridinyl or said salt therof.
• the invention resides in the process which comprises reacting 2-amino-4-PY-phenol with a carbonylating agent, preferably carbonyldiimidazole, to produce 5-PY-benzoxazol-2(3H)-one of formula I, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents.
• a carbonylating agent preferably carbonyldiimidazole
• a composition aspect of the invention resides in the cardiotonic composition for increasing cardiac contractility which comprises a pharmaceutically-acceptable pharmaceutical carrier and, as the active component thereof, a cardiotonically-effective amount of 5-PY-benzoxazol-2(3H)-one or pharmaceutically-acceptable acid-addition or cationic salt thereof, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents.
• Preferred embodiments of this aspect of the invention are the compositions having, as the active component, said compound where PY is 4- or 3-pyridinyl or said salt thereof.
• a method aspect of the invention resides in the method for increasing cardiac contractility in a patient requiring such treatment which comprises administering orally or parenterally in a solid or liquid dosage form to such patient a cardiotonically-effective amount of 5-PY-benzoxazol-2(3H)-one or pharmaceutically-acceptable acid-addition or cationic salt thereof, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, a preferred embodiment being the method using said compound where PY is 4- or 3-pyridinyl.
• lower-alkyl as used herein, e.g., as the meaning of the substituent for PY means alkyl radicals having from 1 to 6 carbon atoms which can be arranged as straight or branched chains, illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, isobutyl, n-amyl, n-hexyl, and the like.
• PY where PY is 4- or 3-pyridinyl having 1 or 2 lower-alkyl substituents are the following: 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (alternatively named 2-methyl-5-pyridinyl), 2,3-dimethyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-hexyl-4-pyridinyl, 2,6-diethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl, 2,6-diisopropyl-4-pyridinyl, 2,6-di-n-hexyl-4-pyridinyl, 2,6-
• the compound of formula I is useful both in the free base form and in the form of acid-addition salts, and, both forms are within the purview of the invention.
• the acid-addition salts are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the base form.
• the acids which can be used to prepare the acid-addition salts include preferably those which produce, when combined with the free base, pharmaceutically-acceptable salts, that is, salts whose anions are relatively innocuous to the animal organism in pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in the free base are not vitiated by side effects ascribable to the anions.
• Appropriate pharmaceutically-acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acid such as lactic acid, acetic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like, giving the hydrochloride, hydrobromide, sulfate, phosphate, sulfamate, lactate, acetate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
• mineral acids such as hydrochlor
• the acid-addition salts of said basic compound of formula I are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
• all acid-addition salts are within the scope of the invention. All acid-addition salts are useful as sources of the free base form even if the particular salt per se is desired only as an intermediate product as for example when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate in preparing a pharmaceutically-acceptable salt by ion exchange procedures.
• compositions of said compound of formula I are those cationic salts derived from strong inorganic or organic bases, e.g., sodium hydroxide, potassium hydroxide, trimethylammonium hydroxide, to produce the corresponding 1- or N- cationic salt, e.g., sodium, potassium, trimethylammonium salt, respectively, that is, the cationic ion being attached to the 1- or N-position of the 2(1H)-pyridinone ring.
• strong inorganic or organic bases e.g., sodium hydroxide, potassium hydroxide, trimethylammonium hydroxide
• the reaction of 2-amino-4-PY-phenol with a carbonylating agent to produce 5-PY-benzoxazol-2(3H)-one is carried out by mixing the reactants in a suitable inert aprotic solvent at room temperature or heating the reaction mixture up to about 100° C.
• the reaction was conveniently run by stirring the reactants, preferably using carbonyldiimidazole as the carbonylating agent, at room temperature in dimethylformide.
• suitable solvents include dioxane, tetrahydrofuran, toluene, and the like.
• carbonyldiimidazole instead of using carbonyldiimidazole as the carbonylating agent, that is, an agent providing carbonyl, there can be used a di-(lower-alkyl) carbonate, e.g., diethyl or dimethyl carbonate, a lower-alkyl, ethyl or methyl, chloroformate or phosgene; when said alkyl chloroformate or phosgene is used as the carbonylating agent, an acid-acceptor, e.g., triethylamine, pyridine, sodium or potassium hydroxide, sodium or potassium carbonate, and the like, should be used to take up the hydrogen chloride formed as a by-product by the reaction.
• an acid-acceptor e.g., triethylamine, pyridine, sodium or potassium hydroxide, sodium or potassium carbonate, and the like.
• the reaction of 2-nitro-4-PY-phenol with a reducing agent to produce 2-amino-4-PY-phenol was conveniently carried out either by catalytic or chemical reductive means.
• this reduction was conveniently run in a suitable solvent, e.g., acetic acid, dimethylformamide, in the presence of a hydrogenation catalyst, e.g., platinum oxide, palladium-on-charcoal, under catalytic hydrogention conditions at ambient temperature (about 20° to 25° C.) until the uptake of hydrogen ceased.
• a hydrogenation catalyst e.g., platinum oxide, palladium-on-charcoal
• Suitable solvents include tetrahydrofuran, dioxane, methanol, ethanol, water (containing a base, e.g., sodium hydroxide, potassium hydroxide, triethylamine, etc.), and the like.
• suitable hydrogenation catalysts include Raney nickel, and the like.
• Chemical reducing agents useful in the reduction of the 2-nitro compound to produce the 2-amino compound include iron and acetic acid, zinc and hydrochloric acid, and the like. The preparation of the 2-amino-4-PY-phenols is illustrated hereinbelow in Examples C-1 through C-7.
• the intermediate 2-nitro-4-PY-phenols are prepared by nitrating the generally known 4-PY-phenols by conventional nitrating procedures, as illustrated hereinbelow in Examples B-1 through B-7.
• the generally known 4-PY-phenols are conveniently prepared by the generally known procedures of converting corresponding 4-PY-benzenamines via aqueous hydrolysis of their diazonium salts, as illustrated hereinbelow in Examples A-1 through A-7.
• Illustrative of a known 4-PY-phenol is 4-(4-methyl-3-pyridinyl)phenol [Chem. Abstrs. 81, 25,571x (1974)].
• 4-(4-pyridinyl)benzeneamine [Forsyth et al. J. Chem. Soc. 1926, 2912 and Heilbron et al., J. Chem. Soc. 1940, 1279], 4-(3-pyridinyl)benzeneamine [Heilbron et al, ibid.] and 4-(2,5-dimethyl-4-pyridinyl)benzeneamine [Prostakov et al., Chem. Abstr. 84, 179,989p (1976)], which are prepared from the corresponding known 4-PY-nitrobenzenes.
• Example A-7 Following the procedure described in Example A-1 but using a molar equivalent quantity of the appropriate 4-PY-benzeneamine in place of 4-(4-pyridinyl)benzeneamine, it is contemplated that the corresponding 4-PY-phenols of Examples A-2 thru A-7 can be obtained.
• Example B-7 Following the procedure described in Example B-1, but using a molar equivalent quantity of the appropriate 4-PY-phenol in place of 4-(4-pyridinyl)-phenol, it is contemplated that the corresponding 2-nitro-4-PY-phenols of Examples B-2 through B-7 can be obtained.
• acid-addition salts of 2-amino-4-(4-pyridinyl)phenol are conveniently prepared by adding to a mixture of 1 g. of 2-amino-4-(4-pyridinyl)phenol in about 20 ml. of aqueous methanol the appropriate acid, e.g., methane-sulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., dimethanesulfonate, sulfate, phosphate, respectively.
• the appropriate acid e.g., methane-sulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid
• the acid-addition salt is conveniently prepared in aqueous solution by adding to water with stirring a molar equivalent quantity each of 2-amino-4-(4-pyridinyl)phenol and the appropriate acid, e.g., lactic acid or hydrochloric acid, to prepare respectively the lactate or hydrochloride salt of 2-amino-4-(4-pyridinyl)phenol in aqueous solution.
• Acid-addition salts of 5-(4-pyridinyl)benzoxazol-2(3H)-one are conveniently prepared by adding to a mixture of 1 g. of 5-(4-pyridinyl)benzoxazol-2(3H)-one in about 20 ml. of aqueous methanol the appropriate acid, e.g., hydrochloric acid, methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., hydrochloride, methanesulfonate, sulfate, phosphate, respectively.
• the appropriate acid e.g., hydrochloric acid, methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid
• the acid-addition salt is conveniently prepared in aqueous solution by adding to water with stirring a molar equivalent quantity each of 5-(4-pyridinyl)benzoxazol-2(3H)-one and the appropriate acid, e.g., lactic acid or hydrochloric acid, to prepare respectively the lactate or hydrochloride salt of 5-(4-pyridinyl)benzoxazol-2(3H)-one in aqueous solution.
• the compounds of formula I or salts at doses of 10, 30 or 100 ⁇ g./ml. were found to cause a significant increase, that is, greater than 25%, in papillary muscle force and a significant increase, that is, greater than 25%, in right atrial force, while causing a lower percentage increase (than that of papillary muscle force and right atrial force) in right atrial rate.
• 5-(4-pyridinyl)benzoxazol-2(3H)-one when tested by said isolated cat atria and papillary muscle procedure was found to cause 86%, 77% and 179% increases in papillary muscle force at 10, 30 and 100 ⁇ g./ml., respectively, and to cause 76%, 86% and 188% increases in right atrial force at the same respective doses.
• the present invention includes within its scope a cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically-acceptable carrier and, as the active component thereof, a cardiotonically-effective amount of 5-PY-benzoxazol-2(3H)-one or pharmaceutically-acceptable acid-addition or cationic salt thereof.
• the invention also includes within its scope the method for increasing cardiac contractility in a patient requiring such treatment which comprises administering to such patient a cardiotonically-effective amount of said 5-PY-benzoxazol-2(3H)-one or pharmaceutically-acceptable acid-addition or cationic salt thereof.
• said compound or salt thereof will normally be administered orally or parenterally in a wide variety of dosage forms.
• Solid compositions for oral administration include compressed tablets, pills, powders and granules.
• at least one of the active compounds is admixed with at least one inert diluent such as starch, calcium carbonate, sucrose or lactose.
• inert diluents such as starch, calcium carbonate, sucrose or lactose.
• These compositions may also contain additional substances other than inert diluents, e.g., lubricating agents, such as magnesium stearate, talc and the like.
• Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents such compositions may also contain adjuvants, such as wetting and suspending agents, and sweetening, flavoring, perfuming and preserving agents. According to the invention, the compounds of oral administration also include capsules of absorbable material, such as gelatin, containing said active component with or without the addition of diluents or excipients.
• Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions.
• organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate.
• These compositions may also contain adjuvants such as stabilizing, preserving, wetting, emulsifying and dispersing agents.
• They may be sterilized, for example by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
• the percentages of active component in said composition and method for increasing cardiac contractility may be varied to that a suitable dosage is obtained.
• the dosage administered to a particular patient is variable, depending upon the clinician's judgement using as the criteria: the route of administration, the duration of treatment, the size and condition of the patient, the potency of the active component and the patient's response thereto.
• An effective dosage amount of active component can thus only be determined by the clinician considering all criteria and utilizing his best judgement on the patient's behalf.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Cardiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Heart & Thoracic Surgery (AREA)
• Hospice & Palliative Care (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Priority Applications (27)

Applications Claiming Priority (1)

Related Child Applications (1)

Publications (1)

Family

ID=22778673

Family Applications (1)

Country Status (26)

Citations (1)

Family Cites Families (1)

• 1980
  • 1980-11-24 US US06/209,416 patent/US4310531A/en not_active Expired - Lifetime
• 1981
  • 1981-10-26 GB GB8132204A patent/GB2098594B/en not_active Expired
  • 1981-10-27 IL IL64129A patent/IL64129A/xx unknown
  • 1981-10-29 ZA ZA817487A patent/ZA817487B/xx unknown
  • 1981-10-30 NZ NZ198819A patent/NZ198819A/en unknown
  • 1981-11-03 PH PH26434A patent/PH17977A/en unknown
  • 1981-11-05 FR FR8120745A patent/FR2494690A1/fr active Granted
  • 1981-11-06 BE BE1/10350A patent/BE891017A/fr not_active IP Right Cessation
  • 1981-11-10 FI FI813550A patent/FI813550A7/fi not_active Application Discontinuation
  • 1981-11-12 AU AU77417/81A patent/AU545707B2/en not_active Expired - Fee Related
  • 1981-11-13 PT PT73986A patent/PT73986B/pt unknown
  • 1981-11-16 GR GR66541A patent/GR78020B/el unknown
  • 1981-11-17 CH CH7393/81A patent/CH652124A5/fr not_active IP Right Cessation
  • 1981-11-17 KR KR1019810004439A patent/KR830007637A/ko not_active Withdrawn
  • 1981-11-17 NL NL8105204A patent/NL8105204A/nl not_active Application Discontinuation
  • 1981-11-17 IT IT25143/81A patent/IT1144937B/it active
  • 1981-11-18 NO NO813911A patent/NO813911L/no unknown
  • 1981-11-18 DK DK510881A patent/DK510881A/da unknown
  • 1981-11-18 SE SE8106871A patent/SE8106871L/xx not_active Application Discontinuation
  • 1981-11-19 JP JP56186107A patent/JPS57116068A/ja active Pending
  • 1981-11-19 AR AR287514A patent/AR231139A1/es active
  • 1981-11-19 AT AT0498981A patent/AT379808B/de not_active IP Right Cessation
  • 1981-11-19 DE DE19813145847 patent/DE3145847A1/de not_active Withdrawn
  • 1981-11-19 LU LU83770A patent/LU83770A1/fr unknown
  • 1981-11-23 ES ES507383A patent/ES8304568A1/es not_active Expired
  • 1981-11-23 CA CA000390671A patent/CA1159835A/en not_active Expired

Patent Citations (1)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events